Despite hundreds of clinical trials and dramatic advances in our understanding of the genetics and molecular biology of the disease, the median survival of patients suffering with glioblastoma has gone from 12 months three decades ago to 15 months today. No wonder that few of the roughly 20,000 glioma patients I have cared for over the years are still alive. Clearly a new way to understand and approach this disease is needed. In this proposal I hypothesize that a major reason for the lack of successful therapies in gliomas is a failure to model the complexity and resulting emergent properties of the ?cancer state?. Our ability to comprehensively understand and ultimately therapeutically manipulate complex cancer phenotypes will require the creation of clinically relevant models that intrinsically embrace that complexity. Given that these parameters are not met by any current model system, it is the intent of this proposal to take a novel approach to cancer research by building a model that for the first time will allow us to study GBM in the laboratory as the human disease that it is. To that end we propose building an in vitro model of the human brain harboring a growing tumor in a patient-specific manner. We have achieved the first iteration of this initiative by successfully generating human cerebral organoids generated from human embryonic stem cell lines and from patient-specific induced pluripotent stem cells. These cerebral organoids have almost all of the correct cell types and correctly oriented neuro-anatomic compartments seen in a 20-weeks of human fetal brain. Moreover, primary patient-derived GBM stem cells grow within their autologous cerebral organoids and form destructive tumors that phenocopy the parental clinical tumor. Likewise, we can form de novo GBMs by introducing genomic aberrations of the patient's original tumor within their own cerebral organoids by using advanced gene editing techniques. I now propose that cerebral organoids, or patient derived ?minibrains,? offer a unique and novel model system for studying GBM by creating a complex ?tumor system? in vitro that largely recapitulates in vivo conditions of tumor growth but in an experimentally manipulable, biologically (clinically) relevant, logistically pragmatic and scientifically rigorous way. This approach will allow us for the first time to mechanistically study clinically apparent emergent phenomenon of GBM, not previously studied, ultimately leading to novel and more effective strategic therapeutic approaches to this devastating disease.